The cytokine interleukin 18 (IL-18) was initially described as an interferon-γ (IFN-γ) inducing factor (Nakamura et al., 1989). It is an early signal in the development of T-lymphocyte helper cell type 1 (TH1) responses. IL-18 acts together with IL-12, IL-2, antigens, mitogens, and possibly further factors, to induce the production of IFN-γ. IL-18 also enhances the production of GM-CSF and IL-2, potentiates anti-CD3 induced T cell proliferation, and increases Fas-mediated killing of natural killer cells.
Mature IL-18 is produced from its precursor by the IL-1β converting enzyme (ICE, caspase-1).
The IL-18 receptor consists of at least two components, IL-18R alpha and IL-18R beta, co-operating in ligand binding. High- and low-affinity binding sites for IL-18 were found in murine IL-12 stimulated T cells (Yoshimoto et al., 1998), suggesting a multiple chain receptor complex. The two receptor subunits that have been identified so far, both belonging to the IL-1 receptor family (Parnet et al., 1996; Kim et al., 2001). The signal transduction of IL-18 involves activation of NF-κB (DiDonato et al., 1997). The IL-18 receptor complex consists of two receptor chains: a ligand-binding chain termed the IL-18Rα chain and a signal-transducing chain termed the IL-18Rβ chain. The IL-18Ralpha chain was initially isolated as a cell surface protein binding to radiolabeled IL-18; the protein was purified and its amino acid sequence revealed identity with a previously reported orphan receptor termed the IL-1R-related protein (IL-1Rrp) (Torigoe et al., 1997).
Recently, a soluble protein having a high affinity for IL-18 has been isolated from human urine, and the human and mouse cDNAs as well as the human gene were cloned (Novick et al., 1999; WO 99/09063). The protein has been designated IL-18 binding protein (IL-18BP).
IL-18BP is not the extracellular domain of one of the known IL18 receptors, but a secreted, naturally circulating protein. It belongs to a novel family of secreted proteins, further including several Poxvirus-encoded proteins (Novick et al., 1999). Urinary as well as recombinant IL-18BP specifically bind IL-18 with a high affinity and modulate the biological affinity of IL-18.
The IL-18BP gene was localized to the human chromosome 11q13, and no exon coding for a transmembrane domain was found in an 8.3 kb genomic sequence. Four splice variants or isoforms of IL-18BP generated by alternative mRNA splicing have been found in humans so far. They were designated IL-18BP a, b, c and d, all sharing the same N-terminus and differing in the C-terminus (Novick et al, 1999). These isoforms vary in their ability to bind IL-18. Of the four, hIL-18BP isoforms a and c are known to have a neutralizing capacity for IL-18. Human IL-18BP isoform binds to murine IL-18.
Peripheral vascular disorders may be arterial (occlusive or functional), venous, combined arteriovenous (e.g. arteriovenous fistula), or lymphatic. Occlusive arterial disease includes peripheral arterial occlusion and Buerger's Disease, also called thromboangiitis obliterans. Functional arterial disorders may be vasospastic (Raynaud's phenomenon and disease, acrocyanosis) or vasodilatory (erythromelalgia). They may be secondary to a local fault in the blood vessels or to disturbances in sympathetic nervous system activity, or may accompany organic vascular disease. Venous diseases include venous thrombosis and varicose veins, combined arteriovenous disorders include arteriovenous fistula, and lymphatic disorders include lymphedema and lipedema.
Peripheral arterial occlusion refers to an occlusion of blood supply to the extremities, generally by atherosclerotic plaques (atheromas), a thrombus, or an embolism.
Peripheral arterial occlusion may result in acute or chronic ischemia. Acute ischemia is caused by a ruptured proximal arteriosclerotic plaque, by acute thrombosis on preexisting atherosclerotic disease, by an embolism from the heart, aorta, or other large vessels, or a dissected aneurysm. Chronic ischemia is caused by gradual enlargement of an atheromatous plaque.
Sustained elevation of blood homocysteine, by damaging endothelial cells, predisposes to premature atherosclerosis of the aorta and its branches, the peripheral arteries, the cerebral arteries, and possibly the coronary arteries. Although homocysteine levels are usually elevated in association with other risk factors, they can be modified by diet and vitamin B supplements.
Clinical syndromes of arterial occlusion depend on the vessel involved, the extent of obstruction, how rapidly occlusion progresses, and whether collateral flow is adequate.
Acute occlusion has a history that includes sudden onset of severe pain, coldness, numbness, and pallor in an extremity. The extremity is cold and pale, and pulses are absent distal to the obstruction. Acute occlusion may cause severe ischemia manifested by sensory and motor loss and eventually (after 6 to 8 h) tender induration of muscles on palpation.
In chronic occlusion, the symptoms are related to the insidious development of tissue ischemia. The initial symptom is intermittent claudication. Symptoms of claudication are pain, ache, cramp, or tired feeling that occurs on walking. These symptoms are most common in the calf but may occur in the foot, thigh, hip, or buttocks.
Eventually, ischemic pain may occur at rest, beginning in the most distal parts of a limb as a severe, unrelenting pain aggravated by elevation and often preventing sleep.
The level of arterial occlusion and the location of intermittent claudication closely correlate, e.g. aortoiliac disease frequently causes claudication in the buttocks, hips, and calves, and the femoral pulses are reduced or absent. In femoropopliteal disease, claudication is typically in the calf, and all pulses below the femoral are absent. In patients with small vessel disease (e.g. thromboangiitis obliterans, diabetes mellitus), femoropopliteal pulses may be present but foot pulses are absent. Pallor of the involved foot after 1 to 2 min of elevation, followed by rubor on dependency, helps confirm arterial insufficiency. Venous filling time on dependency after elevation exceeds the normal limit of 15 sec. If symptoms of claudication occur with good distal pulses, spinal stenosis should be considered in the differential diagnosis.
A severely ischemic foot is painful, cold, and often numb. In chronic cases, the skin may be dry and scaly with poor nail and hair growth. As ischemia worsens, ulceration may appear (typically on the toes or heel, occasionally on the leg), especially after local trauma. Edema is usually not present unless the patient has kept the leg in a dependent position for pain relief, however, a severely ischemic leg may be atrophic. More extensive occlusion may compromise tissue viability, leading to necrosis or gangrene. Ischemia with rubor, pain, and swelling of the foot on dependency may mimic cellulitis or venous insufficiency. Arterial noninvasive tests can clarify the diagnosis.
Among the peripheral vascular diseases, Buerger's Disease (Thromboangiitis Obliterans) is an obliterative disease characterized by inflammatory changes in small and medium-sized arteries and veins.
Buerger's Disease occurs in cigarette smokers, predominantly in men aged 20 to 40. Only about 5% of cases occur in women. The frequency of diagnosis has decreased drastically in recent years because of better understanding of clinical and angiographic characteristics of this disease versus arteriosclerosis obliterans.
Although the cause is unknown, Buerger's Disease has not been documented in nonsmokers, implicating cigarette smoking as a primary etiologic factor, perhaps as a delayed type of hypersensitivity or toxic angiitis. Thromboangiitis obliterans may be a reaction to tobacco by persons with a specific phenotype, because of greater prevalence of HLA-A9 and HLA-B5 in persons with the disease; or an autoimmune disorder with cell-mediated sensitivity to types I and III human collagen, which are constituents of blood vessels.
Unlike atherosclerosis, Buerger's Disease does not involve the coronary arteries.
The disease involves small and medium-sized arteries and, frequently, superficial veins of the extremities in a segmental pattern. Rarely, in advanced disease, vessels in other parts of the body are affected. The pathologic appearance is that of a nonsuppurative panarteritis or panphlebitis with thrombosis of involved vessels. Proliferation of endothelial cells and infiltration of the intimal layer with lymphocytes occur in the acute lesion, but the internal elastic lamina is intact. The thrombus becomes organized and later incompletely recanalizes. The media is well preserved but may be infiltrated with fibroblasts. Because the adventitia usually is more extensively infiltrated with fibroblasts, older lesions show periarterial fibrosis, which may also involve the adjacent vein and nerve.
The symptoms and signs are those of arterial ischemia and of superficial thrombophlebitis. Onset is gradual, starting in the most distal vessels of the upper and lower extremities and progressing proximally, culminating in distal gangrene. The patient may complain of coldness, numbness, tingling, or burning before there is objective evidence of disease. Raynaud's phenomenon is common. Intermittent claudication occurs in the involved extremity (usually the arch of the foot or the leg, but rarely the hand, arm, or thigh). Pain is persistent with more severe ischemia, e.g. in the pregangrenous stage and with ulceration or gangrene. Frequently, sympathetic nerve overactivity is manifested by coldness, excessive sweating, and cyanosis of the involved extremity, probably caused by the severe, persistent pain.
Ischemic ulceration and gangrene, usually of one or more digits, may occur early in the disease but not acutely. Noninvasive studies show severe decreases in blood flow and pressure in affected toes, feet, and fingers. The disease progresses proximally.
Another peripheral vascular disease is peripheral arterial disease, in which patients with lower extremity peripheral arterial disease (PAD) may progress to severe, limb-threatening ischemia. Ischemic rest pain, nonhealing ulcerations, and gangrene are all harbingers of poor outcomes. These patients are at high risk of limb loss. Prompt detection and evaluation of severe limb ischemia followed by efficient revascularization are required for limb salvage and preservation of overall health.
Chronic critical limb ischemia is the end result of arterial occlusive disease, most commonly atherosclerosis. In addition to atherosclerosis in association with hypertension, hypercholesterolemia, cigarette smoking and diabetes less frequent causes of chronic critical limb ischemia include Buerger's disease, or thromboangitis obliterans, and some forms of arteritis.
The development of chronic critical limb ischemia usually requires multiple sites of arterial obstruction that severely reduce blood flow to the tissues. Critical tissue ischemia is manifested clinically as rest pain, non-healing wounds (because of the increased metabolic requirements of wound healing) or tissue necrosis (gangrene).
Ischemic rest pain is classically described as a burning pain in the ball of the foot and toes that is worse at night when the patient is in bed. Ischemic rest pain is located in the foot, where tissue is farthest from the heart and distal to the arterial occlusions. Non-healing wounds are usually found in areas of foot trauma caused by improperly fitting shoes or an injury. A wound is generally considered to be nonhealing if it fails to respond to a four- to 12-week trial of conservative therapy such as regular dressing changes, avoidance of trauma, treatment of infection and debridement of necrotic tissue.
Gangrene is usually found on the toes. It develops when the blood supply is so low that spontaneous necrosis occurs in the most poorly perfused tissues.
While carefully designed conservative therapy can benefit many patients with critical limb ischemia, the severe nature of their disease may lead to consideration of operative intervention. Surgical interventions include revascularization or amputation. If the patient wants to undergo revascularization and is an acceptable operative candidate, arteriography is often performed for further evaluation and planning of revascularization. At some centers, magnetic resonance angiography is used as an alternative or supplement to arteriography to minimize the risk of dye exposure. Limb preservation by means of revascularization is cost-effective, leads to a better quality of life for most patients and is associated with lower perioperative morbidity and mortality than amputation. Limb preservation should be the goal in most patients with chronic critical limb ischemia.
The feasibility of revascularization is determined by the arteriographic findings as well as the availability of a bypass conduit. Angioplasty or stent placement, or both, is most successful with short, proximal lesions, such as those in patients with claudication, but is unlikely to be the only treatment necessary in the setting of critical limb ischemia because of the multilevel nature of the arterial occlusive disease. The ideal bypass conduit is the greater saphenous vein, but other conduits include the lesser saphenous veins, the arm veins or a prosthetic conduit. In most surgical series, three-year bypass patency rates of calf arteries range from 40 percent for prosthetic bypasses to 85 percent for saphenous vein bypasses. In comparison, studies of conservative therapy have demonstrated a 25 to 49 percent success rate with nonhealing wounds and a 50 to 80 percent rate of improvement in ischemic rest pain.
Primary amputation may be indicated in certain patients, such as those with extensive tissue necrosis, life-threatening infection or lesions not amenable to revascularization. The decision to monitor the patient's condition with watchful waiting and conservative management or to perform revascularization or amputation depends on careful assessment of the attendant risks and benefits of surgery versus conservative management.
More importantly, it depends on the patient's interpretation of the invasiveness or appropriateness of the available options. Even patients unable to walk because of their condition may consider amputation inappropriate, and not all patients are motivated to do the work necessary for rehabilitation after amputation. If the decision is made to amputate, the level of amputation should be one that has the greatest likelihood of healing while giving the patient the maximal chance for functional rehabilitation.
Diagnosis of chronic critical limb ischemia involves manifested pain at rest, non-healing wounds and gangrene. Ischemic rest pain is typically described as a burning pain in the arch or distal foot that occurs while the patient is recumbent but is relieved when the patient returns to a position in which the feet are dependent. Objective hemodynamic parameters that support the diagnosis of critical limb ischemia include an ankle-brachial index of 0.4 or less, an ankle systolic pressure of 50 mm Hg or less, or a toe systolic pressure of 30 mm Hg or less. Intervention may include conservative therapy, revascularization or amputation. Progressive gangrene, rapidly enlarging wounds or continuous ischemic rest pain can signify a threat to the limb and suggest the need for revascularization in patients without prohibitive operative risks. Bypass grafts are usually required because of the multilevel and distal nature of the arterial narrowing in critical limb ischemia. Patients with diabetes are more likely than other patients to have distal disease that is less amenable to bypass grafting. Compared with amputation, revascularization is more cost-effective and is associated with better perioperative morbidity and mortality. Limb preservation should be the goal in most patients with critical limb ischemia.
At present, the major treatment of peripheral vascular diseases include invasive treatment such as angioplasty of even limb amputation. Identification of drugs that stimulate peripheral neovascularization without increasing atherosclerotic plaque progression is of major therapeutic importance in this medical field.